Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation.

APPROXIMATELY 10,000 autologous hematopoietic stem cell (HSC) transplants are performed worldwide each year for malignant diseases.1 Results of randomized trials in recent years suggest that high-dose chemotherapy followed by infusion of autologous HSCs can offer prolonged disease-free survival in hematologic malignancies including non-Hodgkin’s lymphoma in relapse,2 acute myelogenous leukemia,3 and multiple myeloma.4 Similarly encouraging results have been seen in the treatment of solid tumors.5,6 After transplantation, reconstitution of bone marrow (BM) consists of two distinct phenomena, numerical recovery of BM cellular elements on the one hand and functional recovery of cellular interactions on the other. Although reappearance of neutrophils and platelets is often considered the endpoint of hematologic recovery after intensive chemotherapy and stem cell transplantation, this ignores the second arm of BM recovery, that of immunological reconstitution. In fact, functional recovery of lymphoid and immune effector cells occurs very gradually, and reconstitution of normal humoral and cellular immunity may take a year or more. Immune reconstitution involves several components of the immune response. These include (1) reappearance of functional B cells, (2) thymic and extra-thymic T-cell development, (3) reconstitution of effector cells including cytotoxic T cells and natural killer (NK) cells, and (4) efficient antigen presentation to reconstitute the pretransplantation immune repertoire. This restoration of immune function is not merely experimental. It may have direct clinical implications: Immediately after the administration of intensive cytotoxic drugs, minimal tumor burden is presumed to be present, providing potentially ideal circumstances to eliminate residual disease altogether by immunotherapeutic means. In this review, several strategies that could lead to enhancement of cellular immune function to take particular advantage of posttransplantation minimal residual disease will be discussed. In addition, the potential to accelerate immune reconstitution and the effect that might have in the therapy of malignant disease will be considered. Although there are similarities in immune reconstitution after allo-BM transplantation (BMT)7,8 and autologous HSCs, alloBMT involves graft-versus-host disease (GVHD) and the use of immunosuppressive therapy to control it, both of which interfere in the early developmental stages of immune reconstitution. Autologous HSC transplantation that entails neither GVHD nor immunosuppressive drugs presents more direct insight into the factors involved in immune reconstitution after grafting.